title: The stimulation of HSD17B7 expression by estradiol provides a powerful feed-forward mechanism for estradiol biosynthesis in breast cancer cells.
abstract: Our laboratory has previously cloned and purified an ovarian protein found to be a novel 17β-hydroxysteroid dehydrogenase type 7 enzyme (HSD17B7) (formerly prolactin receptor-associated protein) that converts the weak estrogen, estrone, to the highly potent estradiol. The regulation of this enzyme has not yet been explored. In this report, we show high expression of HSD17B7 in human ductal carcinoma and breast cancer cell lines and present evidence for a strong up-regulation of this enzyme by estradiol at the level of mRNA, protein expression, and promoter activity in MCF-7 cells. The effect of estradiol is mediated by estrogen receptor (ER)α, whereas ERβ prevents this stimulation. ER antagonists, ICI 182,780 and 4-hydroxytamoxifen, prevent estradiol-induced stimulation of the endogenously expressed HSD17B7, suggesting that these inhibitors not only block estradiol action but also its production. We have identified a -185-bp region of the hsd17b7 promoter that is highly conserved among rat, mouse, and human and confers regulation by estradiol in MCF-7 cells. This region is devoid of a classical estradiol-response element but contains a nuclear factor 1 (NF1) site that is essential for estradiol action. We found that estradiol stimulates the recruitment and DNA binding of NF1 to this region of the hsd17b7 promoter. Furthermore, knockdown of NF1 family members, NF1B, NF1A, and NF1X, completely prevents induction of this gene by estradiol. In summary, our findings demonstrate that estradiol stimulates HSD17B7 transcriptional activity in breast cancer cells through a novel mechanism requiring NF1 and strongly suggest a positive feedback mechanism to increase local estradiol synthesis causing growth of estrogen-dependent breast cancers.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Aurora
authors.initials: A
authors.lastname: Shehu
authors.forename: Constance
authors.initials: C
authors.lastname: Albarracin
authors.forename: Y Sangeeta
authors.initials: YS
authors.lastname: Devi
authors.forename: Kristin
authors.initials: K
authors.lastname: Luther
authors.forename: Julia
authors.initials: J
authors.lastname: Halperin
authors.forename: Jamie
authors.initials: J
authors.lastname: Le
authors.forename: Jifang
authors.initials: J
authors.lastname: Mao
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Duan
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
authors.forename: Geula
authors.initials: G
authors.lastname: Gibori
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000096:biosynthesis*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007106:Immune Sera; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D020218:Response Elements; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007106:Immune Sera; D051839:NFI Transcription Factors; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; C055351:S100A6 protein, human; D004958:Estradiol